Powder material for electrostatic application to a substrate and electrostatic application of the powder material to a substrate

ABSTRACT

This invention concerns a powder material suitable for electrostatic application to a substrate and a method of electrostatically applying said powder material to a substrate. At least some of the particles which constitute the powder material comprise a core and a shell surrounding the core. The shell and core generally have differing compositions and have different chemical and/or physical properties. Components which are likely to be altered can be placed in the core whilst maintaining the shell composition, thus allowing changes in formulation of the powder material without destroying the performance of the material in electrostatic application. The powder material is especially suitable for electrostatic application to pharmaceutical solid dosage forms.

FIELD OF THE INVENTION

[0001] This invention relates to a powder material suitable forelectrostatic application to a substrate, and to a method ofelectrostatically applying the powder material to a substrate. Inparticular, but not exclusively, the invention relates to powdermaterial and its application to the surface of solid dosage forms, forexample tablets, especially pharmaceutical solid dosage forms.

[0002] A “dosage form” can be formed from any material that can beapportioned into individual units; it may be, but is not necessarily, anoral dosage form. Examples of pharmaceutical solid dosage forms includepharmaceutical tablets, pharmaceutical pessaries, pharmaceutical bougiesand pharmaceutical suppositories. The term “pharmaceutical tablet”should be interpreted as covering all pharmaceutical products which areto be taken orally, including pressed tablets, pellets, capsules andspherules. The term “solid dosage form” does not, however, includeproducts such as small pellets and granules where a large number areutilised to provide a single dosage, for example small pellets which arefilled into capsule shells for administration, and granules which arecompressed to form tablets or sprinkled on the food or drink; suchpellets or granules are not themselves each solid dosage forms butrather, when combined together, for example in a capsule or tablet,define in combination a solid dosage form. Examples ofnon-pharmaceutical solid dosage forms include items of confectionery,washing detergent tablets, repellents, herbicides, pesticides andfertilisers.

[0003] The electrostatic application of powder material to a substrateis well known. The electrostatic application of powder material to asolid dosage form is also known. For example, WO 92/14451 describes aprocess in which the cores of pharmaceutical tablets are conveyed on anearthed conveyor belt and electrostatically charged powder is depositedon the cores to form a powder coating on the surface of the cores.

BACKGROUND TO THE INVENTION

[0004] A powder material for electrostatic application to a substrateshould have certain properties. For example, the electrical propertiesof the powder material should be such as to make the powder materialsuitable for electrostatic application, and other properties of thepowder material should be such that the material can be secured to thesubstrate once electrostatic application has taken place.

[0005] WO 96/35413 describes a powder material which is especiallysuitable for electrostatic application to a poorly-conducting(non-metal) substrate such as a pharmaceutical tablet. Because it may bedifficult to find a single component capable of providing the materialwith all the desired properties, the powder material comprises a numberof different components which together are capable of providing thematerial with all or at least as many as possible of the desiredproperties, the components being co-processed to form “compositeparticles”. For example, the powder material may comprise compositeparticles including one component which is fusible to form a continuousfilm on the surface of the substrate, and another component which hasdesirable electrical properties.

[0006] WO 96/35413 also describes a coating material for theelectrostatic coating of a substrate, wherein the coating materialincludes active material. The active material may be one which isphysiologically active, the coating material being applied, for example,to a tablet core containing the same or a different active material orto a core containing no active material. By electrostatically applyingactive material to a surface of the dosage form, it has been found to bepossible to apply accurately very small amounts of active material tothe dosage form, leading to improved dose reproducibility.

[0007] A disadvantage of the above-mentioned powder materials, however,is that they are not readily adaptable to changes in formulation. Theformulation of a powder material may be changed for a number ofdifferent reasons. For example, if the material is a coloured material,there may be a change in the colorant, or if the material is an activematerial, for example a physiologically active material, there may be achange in the type of active material, or in the concentration of thatactive material. Because all the components of the powder material areintimately mixed, any change in the components will alter the material'selectrical properties and hence its performance in electrostaticapplication. Whenever there is a change in formulation, it may thereforebe necessary, for optimum performance, to adjust the content of thecomponent(s) that make the material suitable for electrostaticapplication, or perhaps even to use a different component.

[0008] There is accordingly a need for a method of electrostaticallyapplying a powder material to a substrate, in which the powder materialis more readily adaptable to changes in formulation.

SUMMARY OF THE INVENTION

[0009] The present invention provides a method of electrostaticallyapplying a powder material to a substrate, wherein at least some of theparticles of the material comprise a core and a shell surrounding thecore, the core and the shell having different physical and/or chemicalproperties. Commonly, the majority of the particles of the material and,generally, substantially all the particles of the material comprise acore and a shell.

[0010] Generally, the shell and the core have a different composition.Advantageously, at least one component is present in the shell that isnot present in the core or, especially, at least one component ispresent in the core that is not present in the shell, or both shell andcore contain a component or components that are not found in the core orshell respectively. The shell may, if desired, comprise one or morelayers.

[0011] Where the particles of the powder material of the presentinvention comprise a core and a shell surrounding the core, it ispossible to place those components which are likely to be altered, forexample colorant and active material, in the core, and to provide a moreuniversal shell composition which is suitable for use with various corecompositions, so that alterations may be made to the components that arein the core without substantially affecting the overall suitability ofthe powder material; thus, the shell ensures that the change incomposition of the core does not affect the performance of the materialin electrostatic application. Accordingly, alterations to one componentof the powder material may be made with minimum alteration in theamounts of other components.

[0012] Accordingly, the present invention especially provides a methodof preparing a number of different powder materials for electrostaticapplication to pharmaceutical substrates, the particles of each of thepowder materials comprising a core and a shell surrounding the core,which method comprises, for each powder material, encapsulating thedesired core material, the core material suitably comprising a binderpolymer and one or more additives selected from a colorant, anopacifier, a biologically active material and a filler and optionallyone or more other additives, with a shell material having differentphysical and/or chemical properties from the core material and suitablycomprising a binder polymer and optionally one or more other additives,and wherein the same shell material is used for the different powdermaterials produced.

DETAILED DESCRIPTION OF THE INVENTION

[0013] Generally, the powder material includes a component which isfusible, and that component may be present in the shell or in the coreor in both the shell and the core. Advantageously, the fusible componentis treatable to form a continuous film coating. Examples of suitablecomponents are as follows: polyacrylates, for example polymethacrylates;polyesters; polyurethanes; polyamides, for example nylons; polyureas;polysulphones; polyethers; polystyrene; polyvinylpyrrolidone;biodegradable polymers, for example polycaprolactones, polyanhydrides,polylactides, polyglycolides, polyhydroxybutyrates andpolyhydroxy-valerates; polysaccharides, for example cellulose ethers andcellulose esters; sugar alcohols, for example lactitol, sorbitol,xylitol, galactitol and maltitol; sugars, for example sucrose, dextrose,fructose, xylose and galactose; hydrophobic waxes and oils, for examplevegetable oils and hydrogenated vegetable oils (saturated andunsaturated fatty acids), e.g. hydrogenated castor oil, carnauba wax,and bees wax; hydrophilic waxes; polyalkenes and polyalkene oxides;polyethylene glycol. Clearly there may be other suitable materials, andthe above are given merely as examples. One or more fusible materialsmay be present. Preferred fusible materials generally function as abinder for other components in the powder.

[0014] In general the powder material should contain at least 30%,usually at least 35%, advantageously at least 80%, by weight of materialthat is fusible, and, for example, fusible material may constitute up to95%, e.g. up to 85%, by weight of the powder. Wax, if present, isusually present in an amount of no more than 6%, especially no more than3%, by weight, and especially in an amount of at least 1% by weight, forexample 1 to 6%, especially 1 to 3%, by weight of the powder material.

[0015] Of the materials mentioned above, polymer binders (also referredto as resins) should especially be mentioned. Examples includepolyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, and methacrylate polymers, for example anammonio-methacrylate copolymer, for example those sold under the nameEudragit. Xylitol or other sugar alcohol may be added to the polymerbinder, for example when the polymer binder is insoluble, to promotesolubility.

[0016] Often resin will be present in the core and the shell, with a waxas an optional further fusible component in the core; the presence of awax may, for example, be useful where fusing is to take place by acontact system, for example using a heated roller, or where it isdesired to provide a glossy appearance in the fused film. Sugar alcohol,if used, may be present in the core and/or the shell as appropriate. Thefusible component may comprise a polymer which is cured during thetreatment, for example by irradiation with energy in the gamma, ultraviolet or radio frequency bands. For example, the core may comprisethermosetting material which is liquid at room temperature and which ishardened after application to the substrate.

[0017] Preferably a fusible component is fusible at a temperature of nomore than 250° C., more especially no more than 150° C., at a pressureof no more than 100 lb/sq inch, more especially at atmospheric pressure.

[0018] Where both the shell and the core contain a component which isfusible, those components may be the same or different. Often the coreand shell contain different fusible materials. A shell material may bechosen, for example, for its triboelectric charging properties and/or toprovide mechanical strength to the particles. Other material is chosen,for example, for its good fusibility. Selection of the fusible componentor components used may also be influenced by the end use. For example,it may be desirable to utilise a binder(s) that is fast dissolving, forexample for washing detergent tablets. When different fusible materialsare used, they are preferably compatible so that they can fuse together.

[0019] Preferably, the powder material includes a material having acharge-control function. That functionality may be incorporated into apolymer structure, as in the case of Eudragit resin mentioned above,and/or, for a faster rate of charging, may be provided by a separatecharge-control additive. Material having a charge-control function maybe present in the shell or in the core or in both shell and core.Examples of suitable charge-control agents are as follows: metalsalicylates, for example zinc salicylate, magnesium salicylate andcalcium salicylate; quaternary ammonium salts; benzalkonium chloride;benzethonium chloride; trimethyl tetradecyl ammonium bromide(cetrimide); and cyclodextrins and their adducts. One or morecharge-control agents may be used. Charge-control agent may be present,for example, in an amount of up to 10% by weight, especially at least 1%by weight, for example from 1-2% by weight, based on the total weight ofthe powder material. The presence of charge-control agent in the coreshould especially be mentioned; in some cases, the presence of thismaterial in the core only can be effective to establish a base charginglevel, despite encapsulation.

[0020] The powder material may also include a flow aid present at theouter surface of the shell. The flow aid reduces the cohesive and/orother forces between the particles of the material to improve theflowability of the powder. The component may be present on the surfaceof the shell although in addition some may be embedded in the surface ofthe shell. Suitable flow aids (which are also known as “surfaceadditives”) are, for example, as follows: colloidal silica; metaloxides, e.g. fumed titanium dioxide, zinc oxide or alumina; metalstearates, e.g. zinc, magnesium or calcium stearate; talc; functionaland non-functional waxes, and polymer beads, e.g. poly-methylmethacrylate beads, fluoropolymer beads and the like. Such materials mayalso enhance tribocharging. A mixture of flow aids, for example silicaand titanium dioxide, should especially be mentioned. The powdermaterial may contain, for example, 0 to 3% by weight, advantageously atleast 0.1%, e.g. 0.2 to 2.5%, by weight of surface additive flow aid.

[0021] Often the powder material includes a colorant and/or anopacifier. Such components are preferably present in the core, althougheach may alternatively or in addition be present in the shell. Examplesof suitable colorants and opacifiers are as follows: metal oxides, e.g.titanium dioxide, iron oxides; aluminium lakes, for example, indigocarmine, sunset yellow and tartrazine; approved food dyes; naturalpigments. A mixture of such materials may be used if desired. Opacifierpreferably constitutes no more than 50%, especially no more than 40%,more especially no more than 30%, for example no more than 10%, byweight of the powder material, and may be used, for example, in anamount of at least 5% by weight of the powder. Titanium dioxide is anespecially useful opacifier, providing white colour and having goodhiding power and tinctorial strength. Colorant present with opacifiermay, for example, constitute no more than 10%, preferably from 1 to 5%,by weight of the powder. If there is no opacifier, the colorant may be,for example, 1 to 15%, e.g. 2-15%, especially 2-10%, by weight of thepowder. To achieve optimum colour, amounts of up to 40% by weight ofcolorant may be needed in some cases, for example if inorganic pigments,e.g. iron oxides, are used. However, the powder material usuallycontains, for example, from 0 to 25% by weight in total of colorantand/or opacifier.

[0022] The powder material may also include a dispersing agent, forexample a lecithin. The dispersing agent is preferably present with thecolorant/opacifier (that is, preferably in the core), serving to improvethe dispersion of the colorant and opacifier, more especially whentitanium dioxide is used. The dispersing component is preferably asurfactant which may be anionic, cationic or non-ionic, but may beanother compound which would not usually be referred to as a“surfactant” but has a similar effect. The dispersing component may be aco-solvent. The dispersing component may be one or more of, for example,sodium lauryl sulphate, docusate sodium, Tweens (sorbitan fatty acidesters), polyoxamers and cetostearyl alcohol. Preferably, the powdermaterial includes at lest 0.5%, e.g. at least 1%, for example from 2% to5%, by weight of dispersing component, based on the weight of the powdermaterial. Most often it is about 10% by weight of the colorant+opacifiercontent.

[0023] Where the coating material is used for “immediate” releasetablets, the powder coating material advantageously includes adisintegrant which may disrupt the coating.

[0024] The disintegrant may be one which swells rapidly and extensivelyon contact with moisture, thereby disrupting the coating. Somedisintegrants may swell to become up to 40 times their original volumewithin seconds. Examples of suitable disintegrants include sodium starchglycolate (cross-linked) and sodium carboxymethyl cellulose(cross-linked).

[0025] Alternatively, or in addition, the disintegrant may be of awicking-type which allows penetration of moisture through the coating tothe substrate core, but which prevents moisture moving from thesubstrate core back through the coating, thereby causing rupture of thecoating. Examples of suitable disintegrants of the wicking type includenative starch and cross-linked polyvinylpyrrolidone (crosprovidone).

[0026] The disintegrant may be a gas-producing type, for example sodiumcarbonate, sodium hydrogen carbonate or sodium glycinate.

[0027] A disintegrant, if present, may be found in the shell and/orcore, more especially in the core. There may, for example, be at least0.5% by weight of disintegrant.

[0028] Preferably, the powder coating material contains no more than 10%by weight of disintegrant. Preferably, the powder contains no more than5%, preferably no more than 2%, more preferably no more than 1%, mostpreferably about 0.5%, by weight of disintegrant.

[0029] The powder material may also include a plasticiser, if necessary,to provide appropriate. Theological properties. A plasticiser may bepresent in the core and/or the shell, but usually, if present, aplasticiser is included with resin used for the core to provideappropriate rheological properties, for example for preparation of thecore by extrusion in a melt extruder. Examples of suitable plasticisersare ethyl citrate and polyethylene glycol having a molecular weight lessthan polyethylene glycol 6000.

[0030] A plasticiser may be used with a resin in an amount, for example,of up to 50% by weight of the total of that resin and plasticiser, theamount depending inter alia on the particular plasticiser used. Thus,the shell can contain an amount of up to 50% by weight of plasticiser,calculated on the weight of the shell resin and shell plasticiser,and/or the core can contain an amount of up to 50% by weight ofplasticiser, calculated on the weight of the core resin and coreplasticiser, although usually any plasticiser is present only in thecore. Plasticiser may be present, for example, in an amount of at least2% by weight based on the weight of the total powder material

[0031] Where the powder material is to be applied to a dosage form fororal administration, the powder coating material may further include oneor more taste modifiers, for example aspartame, acesulfame k,cyclamates, saccharin, sugars and sugar alcohols or flavourings, presentin the core and/or the shell, but especially in the core. Preferablythere is no more than 5%, more preferably no more than 1%, of flavouringbased on the weight of the powder material, but larger or smalleramounts may be appropriate, depending on the particular taste modifierused.

[0032] In a preferred embodiment of the invention, the powder materialincludes active material, preferably present in the core, although suchmaterial may alternatively or in addition be present in the shell. Theactive material may comprise one or more compounds.

[0033] The powder material comprising active material may be applied,for example, to a solid dosage form containing the same or a differentactive material, or may be applied to a solid dosage form containing noactive material.

[0034] The active material may be, for example, a biologically activematerial, that is a material which increases or decreases the rate of aprocess in a biological environment, and a biologically active materialmay be one which is physiologically active. Thus, active materialsinclude those materials which are administered to the human or animalbody, for example for the prevention and/or treatment of disease, aswell as those administered in connection with a diagnostic or otherinvestigation. The coating material comprising biologically activematerial may be applied to, for example, a substrate core containing thesame or a different biologically active material, or may be applied to acore containing no active material.

[0035] The active material may comprise, for example, acid-peptic andmotility-influencing agents, laxatives, anti-diarrhoeials, colo-rectalagents, pancreatic enzymes and bile acids, antiarrhythmics,antianginals, diuretics, anti-hypertensives, hypertensives,anti-coagulants, anti-thrombotics, fibrinolytics, haemostatics,hypolipidaemic agents, anti-anaemia and neutropenia agents, hypnotics,anxiolytics, anti-psychotics, anti-depressants, anti-emetics,anti-convulsants, CNS stimulants, analgesics, anti-pyretics,anti-migraine agents, non-steroidal anti-inflammatory agents, and otheranti-rheumatics, anti-gout agents, muscle relaxants, neuro-muscularagents, steroids, hypoglycaemic agents, hyperglycaemic agents,antibiotics, anti-tuberculous drugs, anti-fungals, anti-parasite drugs,anti-malarials, anti-virals, immunosuppressants, immune modulators,nutritional agents, minerals, vitamins, electrolytes, anti-obesitydrugs, anorectic agents, appetite suppressants, appetite stimulants,anti-allergenics, e.g. anti-histamines, bronchodilators, expectorants,anti-tussives, mucolytics, decongestants, anti-glaucoma agents, oralcontraceptive agents, diagnostic agents, anti-neoplastic agents, drugsfor treating drug-dependence, agents to combat auto-immune diseases,anti-cancer drugs, anticholinergic drugs, drugs for treating infertilityand for other treatments of the female reproductive system and fortreating male sex disorders, and/or drugs for treating incontinence.

[0036] In the case of washing powder tablets, the active material maybe, for example, detergent, enzymes, bleach and/or fabric softener.

[0037] Active material for use in agriculture may be, for example, aninsecticide, herbicide, fertiliser or pesticide, for example slugkiller. Other active material may be, for example, insect repellent.

[0038] Where the uncoated dosage form does not contain active material,the amount of active material in the coating material applied to eachdosage form will usually correspond to one dose of the active componentor to a simple fraction of the single standard dose, for example ½ or ⅓of a single standard dose of the active material. Alternatively, sincethere is often a need for a range of dosages of a particular activematerial, different amounts of active material may be applied to astandard dosage form optionally containing the minimum standard dosage,to provide a supply of dosage forms with a range of different dosages.It will be understood that the absolute quantity of active materialapplied to any dosage form will depend inter alia on the activecomponent used and the number of solid dosage forms to be used together,for example, for a pharmaceutical, the number of dosage forms to betaken by the patient for each dose. The active material may be, forexample, up to 50%, for example up to 30 or 40%, by weight, and, forexample, at least 0.5% by weight, preferably at least 1% by weight, ofthe total weight of the powder material. With very active pharmaceuticalmaterial a much smaller proportion may be appropriate.

[0039] If desired, the powder material may further include a filler ordiluent, present in the core and/or the shell. Suitable fillers anddiluents are essentially inert and low-cost materials with generallylittle effect on the colour or other properties of the powder. Examplesare as follows: alginic acid; bentonite; calcium carbonate; kaolin;talc; magnesium aluminium silicate; and magnesium carbonate. Filler maybe used, for example, interchangeably with active material in thepreparation of a range of powder materials with different activematerial contents. For example, a formulation used as a basis for arange of powders may be supplemented by a constant amount of furthermaterial consisting of active material, active material and filler, orfiller. Thus, for example, a basic formulation which constitutes 60% ofthe final powder material may contain, for example, an additional 40%active material, 30% active material plus 10% filler, 20% activematerial plus 20% filler, or 10% active material plus 30% filler, thepercentages being calculated on the final powder material in each case.

[0040] Although it is preferable for the core to contain all of theingredients which might be altered, that may not always be possible. Forexample, the powder material may comprise a very high proportion ofactive material, for example, up to 60% active material, which wouldresult in unacceptably large particles it the core were also to containall the other ingredients that might be altered. In such cases, forexample, the shell may therefore contain additional ingredients, forexample, colorant.

[0041] The proportions in which the components of the powder materialare mixed is largely dependent on the materials comprising the powdermaterial and the nature of the substrate to be coated. The proportionswill be adjusted so that the desired properties of the powder materialare obtained. Examples of suitable proportions for a powder materialwould be:

[0042] Powder Materials Not Containing an Active Material:

[0043] Composition 1

[0044] 83% by weight resin,

[0045] 0-3% by weight wax,

[0046] 11-14% by weight inorganic colorant,

[0047] 1-2% by weight charge-control agent,

[0048] 1% by weight flow aid (external additive).

[0049] Composition 2

[0050] 90% by weight resin,

[0051] 2% by weight wax,

[0052] 5% by weight colorant,

[0053] 2% by weight charge-control agent,

[0054] 1% by weight flow aid (external additive).

[0055] Composition 3

[0056] 60% by weight resin having charge-control functionality

[0057] 20% by weight xylitol

[0058] 15% by weight opacifier

[0059] 3.5% by weight colorant,

[0060] 1.5% by weight dispersant

[0061] Composition 4

[0062] 83% by weight resin

[0063] 10% by weight opacifier

[0064] 2% by weight colorant,

[0065] 2% by weight dispersant

[0066] 2% by weight charge-control agent

[0067] 0.5% by weight disintegrant

[0068] 0.5% by weight flow aid (external additive)

[0069] Powder Material Containing an Active Material

[0070] Composition 5

[0071] 40% by weight resin(s)

[0072] 50% by weight active material

[0073] 2% by weight wax,

[0074] 5% by weight colorant,

[0075] 2% by weight charge-control agent,

[0076] 1% by weight flow aid (external additive).

[0077] Composition 6

[0078] 45% by weight fusible component having charge-controlfunctionality

[0079] 40% by weight active material

[0080] 5% by weight filler

[0081] 5% by weight opacifier,

[0082] 1% by weight colorant

[0083] 1.5% by weight dispersant

[0084] 1% by weight charge-control agent

[0085] 0.5% by weight taste modifier

[0086] 1% by weight flow aid (external additive)

[0087] Composition 7

[0088] 45% by weight fusible component having charge-controlfunctionality

[0089] 30% by weight active material

[0090] 15% by weight filler

[0091] 5% by weight opacifier

[0092] 1% by weight colorant

[0093] 1.5% by weight dispersant,

[0094] 1% by weight charge-control agent

[0095] 0.5% by weight taste modifier

[0096] 1% by weight flow aid (external additive)

[0097] If necessary, up to 50% by weight of the resin may be replaced bysuitable placticiser.

[0098] The examples are provided as a guide only and are not meant todepict the limits of the invention.

[0099] In one embodiment, advantageously, the content of material in thecore is maximised, with the shell being of minimum thickness consistentwith its having a protecting and pacifying function to ensure the powdermaterial has suitable mechanical and electrostatic properties. Forexample, the core may comprise binder and optionally one or more furthermaterials selected from other fusible material, colorant, opacifier,dispersant, charge-control agent, disintegrant, wax, plasticiser, tastemodifier, active material and filler, and the shell may comprise binderand optionally one or more further materials selected from other fusiblematerial, colorant, dispersant, active material and charge-controlagent. 10 to 20%, e.g. 10%, of the powder may, for example, be used tomake up the shell. In one embodiment this is made up predominantly ofresin.

[0100] Thus, for example, in the examples given above, usually the wax,colorant/opacifier, dispersant, disintegrant, filler and taste modifieras applicable, will be present in the core, as will the majority of theresin and active material when present. The xylitol may be present inthe core and/or shell according, for example, to solubilityrequirements. Charge-control agent may also be present in the shelland/or the core. The shell may consist, for example, of resin. Forexample, the shell, consisting of resin, may be 10% of the powder, withthe remaining resin, constituting 73%, 80%, 40%, 73%, 30%, 35% or 35% ofthe powder, respectively, being present in the core.

[0101] The particle size of the powder material has an important effecton the behaviour of the material in electrostatic application. Althoughmaterials having a small particle size are recognised as havingdisadvantages such as being more difficult to produce and to handle byvirtue of the materials' cohesiveness, such materials have specialbenefits for electrostatic application and the benefits may more thancounter the disadvantages. For example, the high surface-to-mass ratioprovided by a small particle increases the electrostatic forces on theparticle in comparison to the inertial forces. Increasing the force on aparticle has the benefit of increasing the force that causes it to moveinto contact with the substrate, whilst a reduction in the inertiareduces the force needed to accelerate a particle and reduces thelikelihood of a particle arriving at the substrate bouncing back off thesubstrate. However, very small particle sizes may not be achievablewhere the coating material comprises a high proportion of a particularingredient, for example a high proportion of active material.

[0102] Preferably, at least 50% by volume of the particles of thematerial have a particle size no more than 10 μm. Advantageously, atleast 50% by volume of the particles of the material have a particlesize in the range of 5 μm to 40 μm. More advantageously, at least 50% byvolume of the particles of the material have a particle size in therange of 10 to 25 μm.

[0103] Powder having a narrow range of particle size should especiallybe mentioned. Particle size distribution may be quoted, for example, interms of the Geometric Standard Deviation (“GSD”) figures d₉₀/d₅₀ ord₅₀/d₁₀ where d₉₀ denotes the particle size at which 90% by volume ofthe particles are below this figure (and 10% are above), d₁₀ representsthe particle size at which 10% by volume of the particles are below thisfigure (and 90% are above), and d₅₀ represents the mean particle size.Advantageously, the mean (d₅₀) is in the range of from 5 to 40 μm, forexample from 10 to 25 μm. Preferably, d₉₀ /d₅₀ is no more than 1.5,especially no more than 1.35, more especially no more than 1.32, forexample in the range of from 1.2 to 1.5, especially 1.25 to 1.35, moreespecially 1.27 to 1.32, the particle sizes being measured, for example,by Coulter Counter. Thus, for example, the powder may have d₅₀=10 μm,d₉₀=13 μm, d₁₀=7 μm, so that d₉₀/d₅₀=1.3 and d₅₀/d₁₀=1.4.

[0104] For any particular electrostatic application method there will bean optimum particle size. Accordingly, even where there are changes informulation, alterations in particle size should be avoided if possible.Particle size may be kept constant by altering the relative sizes of theshell and the core. For example, if the amount of active material in thecore is increased (thereby increasing the core volume), the thickness ofthe shell may be decreased to compensate.

[0105] Preferably, the shell has a thickness in the range of 0.1 μm to 5μm. Advantageously, the shell has a thickness in the range of 0.1 μm to1.5 μm. A preferred minimum thickness is 0.2 μm; a preferred maximum is1 μm. Thus, advantageously, the shell has a thickness in the range of0.2 μm to 1 μm. If there are several layers comprising the shell, eachshell layer will often have the above-described thicknesses, althoughthe use of thinner layers is also possible. Shell thickness maycorrespond, for example, to one of the lines shown on the accompanyingFIG. 1, which is a graph showing relationships between mean thickness ofthe shell and particle diameter for different proportions by weight ofshell in relation to the whole powder. For example, for a powder of meanparticle size 5 μm, with mean shell thickness 0.3 to 0.5 μm (which willprovide good mechanical protection for a core of soft material), theshell may constitute approximately 30 to 45% by weight of the powder.For a powder of larger mean particle size, the same shell thickness maybe obtained with a smaller proportion of shell in the total powder.Thus, for a powder with mean particle size 20 μm, the same mean shellthickness can be obtained with about 8 to 14% shell. With 10% shell, ashell thickness >0.3 μm is obtained with a mean particle size >15 μm;with 20% shell and a shell thickness >0.3 μm, the mean particle sizewill be >7.5 μm.

[0106] Preferably, the powder material is fusible. Advantageously, thepowder material is treatable to form a continuous film coating.

[0107] It is important that the powder can be fused or treated withoutdegradation of any active material in the powder and without degradationof the substrate. For example, many pharmaceutical substrates aresensitive to heat, particularly pharmaceutical tablet cores, which maycontain organic materials. The desired temperature at which the powdermaterial is treatable will therefore depend on the material making upthe substrate. For some materials it may be possible for the treatmentstep to involve temperatures up to and above 250° C. Preferably,however, the powder material is fusible at a pressure of less than 100lb/sq inch, preferably at atmospheric pressure, at a temperature of lessthan 200° C., and most commonly below 150° C., and often at least 80°C., for example in the range of from 120 to 140° C.

[0108] Generally, both shell and core contain fusible material, and thefusible material in both shell and core is melted on application to thesubstrate. If, however, the shell contains a very high melting polymerwhich is not melted on the substrate, the shell must be ruptured torelease the core material. Rupture may be brought about by pressureand/or by expansion of the core under the action of heat. Alternatively,if the core does not contain fusible material which melts, the shellshould include fusible material which will act as binder for the corematerial.

[0109] Fusing of the powder material may be carried out by any of anumber of different fusing methods. If desired, rupture of the shell andfusing of the material may be carried out in a single step. The powdermaterial is preferably fused by changing the temperature of the powder,for example by radiant fusing using electromagnetic radiation, forexample infra red radiation or ultra-violet radiation, or conduction orinduction, or by flash fusing. The amount of heat required may bereduced by applying pressure to the powder material, for example by coldpressure fusing or hot roll fusing. The powder material may also befused by dissolution of the shell, for example by solvent vapour fusingwhere the powder is exposed to solvent vapour.

[0110] Preferably, the powder material has a glass transitiontemperature (Tg) in the range of 40° C. to 120° C. Advantageously, thematerial has a Tg in the range of 50° C. to 100° C. A preferred minimumTg is 55° C., and a preferred maximum Tg is 70° C. Accordingly, moreadvantageously, the material has a Tg in the range of 55° C. to 70° C.Generally, the powder material should be heated to a temperature aboveits softening point, and then allowed to cool to a temperature below itsTg.

[0111] Advantageously, the powder material once fused is soluble inaqueous media and usually this will be at a temperature of 60° C. orbelow, for example at body temperature in the case of a pharmaceuticaluse. It may, for example, be soluble in neutral aqueous media, but itmay be soluble in only a selected range of pH, for example pH 3 to pH 6or pH 8 to pH 14 This can be especially useful for pharmaceutical use,where a drug is targeted to a particular area of the body.

[0112] Preferably, the substrate on which the powder is deposited ispoorly conducting. Especially it is a non-metal substrate, and moreespecially is a solid dosage form, for example a tablet. Advantageously,the substrate is a pharmaceutical solid dosage form, more especially anoral pharmaceutical solid dosage form, preferably a tablet.

[0113] Preferably, the pharmaceutical solid dosage form is for humanuse.

[0114] Where the powder material is to be applied to a pharmaceuticalsolid dosage form, the powder material should of course bepharmaceutically acceptable.

[0115] The invention is, however, also of applicability to the coatingof other dosage forms, which coated forms release a set quantity ofactive material on utilisation in their intended environment.

[0116] Any suitable method may be used to apply the powder materialelectrostatically to the substrate. For example, the powder may beapplied by spraying electrostatically charged powder material onto thesubstrate, or by holding the powder material at a potential differenceto the substrate sufficient to cause the powder material to be attractedthereto. Thus, the substrate may be earthed. Preferably, however, thesubstrate has an electrostatic charge opposite to the electrostaticcharge on the powder material. The powder material may have a permanentor temporary net charge. Any suitable method may be used to charge thepowder material. Advantageously, the electrostatic charge on the powdermaterial is applied by triboelectric charging (as is common inconventional photocopying) or corona charging. The use of acharge-control agent encourages the particle to charge to a particularsign of charge and to a particular magnitude of charge. The method ofthe present invention is not, however, restricted to use with anyparticular type of electrostatic application method or apparatus.Examples of suitable methods and apparatus are described in WO 96/35516and in our copending application PCT/US00/33962.

[0117] The present invention also provides a substrate to which powdermaterial of the present invention has been applied by a methodcomprising an electrostatic application step.

[0118] The present invention further provides a powder material suitablefor electrostatic application to a substrate, wherein at least some ofthe particles of the material comprise a core and a shell surroundingthe core, the core and the shell having different physical and/orchemical properties.

[0119] The present invention also provides a powder material suitablefor electrostatic application to a substrate, wherein at least some ofthe particles of the material comprise a core and a shell surroundingthe core, the material of the core and the shell having differentphysical and/or chemical properties, wherein at least one componentpresent in the core is not present in the shell and at least onecomponent present in the shell is not present in the core and whereinthe powder material is fusible at a temperature of no more than 150° C.at atmospheric pressure to form a continuous film coating, is soluble inaqueous media and includes a charge-control agent or a polymer havingcharge-control functionality

[0120] Powder materials comprising particles having a core and a shellsurrounding that core are known in various fields. For example, in thepharmaceutical field, a shell has been used to mask the taste of coreingredients, or to control release of core ingredients.

[0121] Various techniques for forming a powder material comprisingparticles having a core and a shell surrounding that core are known. Forexample, aspirin has been encapsulated by gelatin coacervation, bydispersing the aspirin with mineral oil in an aqueous gelatin solutionand inducing phase separation by the addition of isopropanol andtemperature reduction. Hardening was done using a formaldehyde solution.

[0122] The first step in preparing such a material is formation of thecore. The core may be formed by mixing together the components of thecore, and then converting the mixture into particles. The components ofthe core may be mixed together by, for example, melt blending or bydissolving or dispersing the components in water or some other solvent.A melt blend may then be extruded, broken into chips and ground to anappropriate particle size. A solution or dispersion may be convertedinto particles by, for example, wet granulation, spray drying, spraycongealing, cryogenic jetting or electro-dispersion.

[0123] The second step in preparing such a material is formation of theshell by coating the core with shell material.

[0124] The shell may be formed by chemical methods, for example byinterfacial or conventional in situ polymerisation, coacervation, orprecipitation, by spray drying of a solution or melt, centrifugalextrusion or vacuum deposition.

[0125] In coacervation, a solution of the shell components is caused tocoacervate by addition of a coacervating agent, for example gelatin, andthe coacervate is then deposited on cores which are dispersed in thesolution, the coacervate merging on the surface of the cores to form acoating. The coated cores are then isolated by filtration and dried.Examples of types of coacervating agent include a miscible non-solventfor the shell, a pH-adjusting solution, or an ionic solution that willprecipitate the shell.

[0126] In interfacial polymerisation, for example, a solution of theshell components comprising one or more monomers for the core and afirst shell monomer is emulsified by addition of an emulsifier to formemulsified droplets which are dispersed in water or a non-solvent forthe core, and further shell monomer is added which is soluble in thewater or the non-solvent for the core. After formation of the shell byinterfacial polymerisation, free radical polymerisation of the monomeror monomers in the core can be initiated and completed. In conventionalemulsion polymerisation in contrast, a monomer is polymerised around analready-formed core particle.

[0127] Physical methods may also be used for formation of the shell.

[0128] Using a Nara hybridiser, for example, smaller particles, forexample of up to 0.3 micron diameter, may be applied to the surface of alarger core particle, and made to coalesce, for example by applicationof heat, to form a film. Monolayer shells and multilayer shells may becreated in this way if desired. For example, with an oxygen-sensitivematerial in the core or in one layer of shell, it may be desired toprovide an intermediate air-impermeable covering layer with a furthertop layer of high mechanical strength.

[0129] Multiple shells may also be made by other methods, for examplecoacervation.

[0130] In a different embodiment, the shell polymer may be added to adispersion or suspension of core particles in a solvent for the shellpolymer which is a non-solvent for the core particles. The mixture sprayis subsequently dried to deposit the shell polymer on the core.

[0131] A surface additive component for the outer surface of the shellmay be applied in a third step, for example by dry milling or finepowder impaction. This may be carried out, as a batch process, forexample in a hybridiser (a suitable one is the Nara hybridiser), or in aHenschel blender or by a continuous process, for example by amagnetically agitated impact coating process. As will be understood inthe art, the process should be operated to ensure sufficient surfaceadditive adheres to the outside of the particle, rather than becomingburied within the particle. In the case of the Nara hybridiser, forexample, routine adjustment of the intensity of mixing (the rotationspeed), the time of mixing and the temperature ensure the process isoptimised to give the desired result.

[0132] The particle size of the powder material of the present inventionwill be determined predominantly by the size of the core, which isitself determined predominantly by the method selected to produce thecore. Accordingly, a method should be selected which will produce coresof the desired size. When a chemical method of preparation is usedinvolving surfactant (a suitable surfactant is polyvinyl alcohol), sizewill be influenced by the amount of surfactant and by the degree ofagitation. Alternatively, cores of unspecified size may be prepared, andthen passed through one or more sieves to separate out cores of thedesired size. For example, sieves of mesh size 7 μm and 15 μm may beused to obtain a powder having particles varying in size between theselimits.

[0133] A further factor affecting the particle size of the powdermaterial is the solids loading of the shell solution. Accordingly, thesolids loading of the shell should be selected to produce particles ofthe desired size.

[0134] The Examples which follow illustrate the invention, percentagecompositions being percentages by weight, and particle size percentagesbeing by volume.

EXAMPLES Example 1

[0135] Core Core Resin: Polyvinyl pyrrolidone 40% Colorant: SunsetYellow  5% Opacifier: Titanium dioxide 10% Charge Control Agent:Cetrimide  1% Microcrystalline Wax  3% Active Material 30% Shell Shellresin: Eudragit E100 10% Surface additives Hydrophilic fumed silica0.5%  Fumed titanium dioxide 0.5% 

[0136] Preparation of the Core

[0137] The core materials are pre-mixed in a Littleford Blender orV-Mixer to ensure a uniform blend is formed, and then fed to-a twinscrew extruder to melt blend the material and to adequately disperse thecomponents in the resin.

[0138] The cooled extrudate is chipped into large particles (approx. 800microns in size) which are used as the feed for an air jet mill(micronizer). They are jetted to a mean volume particle size of 10microns and classified to remove essentially all particles above 14microns and all particles below 6 microns.

[0139] Preparation of Microcapsules

[0140] The core particles (18 grams) are dispersed into hexane (82 ml)using a high shear dispersion device such as a Brinkmann Homogenizer orKady Mill. The concentration of particles in hexane is 18% solids.

[0141] In a separate vessel there is formed a 10% solution of EudragitE100 in isopropanol. The solution of Eudragit E100 (20 ml) is addedslowly and dropwise to the suspension of core particles in hexane. TheEudragit resin separates from solution and is deposited as a thin (0.2micron) shell surrounding the individual particles.

[0142] The particles are isolated by filtration, and dried at 40 degreesC. under vacuum to remove traces of solvents (isopropanol and hexane).

[0143] Surface Treatment

[0144] The microcapsule particles, having the core-shell structure, areplaced in a Waring Blender together with the surface additives andblended at high speed for a thirty second period, and then for a secondsequential thirty second period to ensure that the microparticulateadditives are both firmly attached and well distributed on themicrocapsules.

Example 2

[0145] Core Core Resin: Hydroxypropyl methylcellulose 40% acetatesuccinate Plasticiser: Triethyl citrate 29.6%   Charge Control Agent:Benzalkonium chloride  1% Opacifier: Titanium dioxide 10% Colorant:Indigo Carmine 2.5%  Colorant: Sunset Yellow 2.5%  Wax: Carnauba Wax(m.p. 86° C.)  4% Shell Shell Resin: Eudragit (High Tg)  9% ChargeControl Agent: Benzalkonium chloride  1% Surface additive HydrophilicFumed Silica 0.4% 

[0146] Preparation of Core

[0147] The core materials are pre-mixed in a Littleford Blender orV-Mixer to ensure a uniform blend is formed, and then blended togetherusing a heated Triple Roll Mill to melt blend the material and toadequately disperse the components in the resin.

[0148] The cooled solid blend is chipped into large particles (approx.800 microns in size) which are used as the feed for an air jet mill(micronizer). They are jetted to a mean volume particle size of 10microns and classified to remove essentially all particles above 14microns and all particles below 6 microns.

[0149] Preparation of Microcapsules

[0150] The core particles (18 grams) are dispersed into hexane (82 ml)using a high shear dispersion device such as a Brinkmann Homogenizer orKady Mill. The concentration of particles in hexane is 18% solids.

[0151] In a separate vessel there is formed a 10% solution of Eudragit(High Tg grade) in isopropanol.

[0152] The solution of Eudragit (20 ml) is added slowly and dropwise tothe suspension of core particles in hexane. The Eudragit resin separatesfrom solution and is deposited as a thin (0.2 micron) shell surroundingthe individual particles.

[0153] The particles are isolated by filtration, and dried at 40 degreesC. under vacuum to remove traces of solvents (isopropanol and hexane).

[0154] Surface Treatment

[0155] The microcapsule particles, having the core-shell structure, areplaced in a Waring Blender together with the surface additives andblended at high speed for a thirty second period, and then for a secondsequential thirty second period to ensure that the microparticulateadditives are both firmly attached and well distributed on the surfaceof the microcapsules.

Example 3

[0156] Core Core Resin: Cellulose acetate phthalate 20% Plasticiser:Triethyl citrate 15% Opacifier: Titanium dioxide 10% Charge controlAgent/Dispersant: Lecithin  1% Colorant: Red Food Dye  4% Activematerial 20% Inert Filler: Magnesium aluminium silicate 15% Shell ShellResin: Polyvinyl pyrrolidone 14.5%   Surface additives Alumina 0.25%  Silica 0.25%  

[0157] Preparation of Core

[0158] The core materials are melt blended using a Banbury mixer, andthe crude melt blend is further melt blended by dropping the melt intothe mixing zone of a heated double roll mill and subjecting the materialto several cuts along the roller and re-feeding into the mixing zone.

[0159] After dispersion of the components of the core into the coreresin had been achieved, the material was cooled and pulverized in aFitz mill (hammer mill) to reduce the particle size to approximately 500microns.

[0160] The 500 micron powder is used as the feed for an Alpine Jet millequipped with a classifier to produce core particles of mean volumediameter (d50) of 8 micron, and a particle size distribution 1.32(d84/d50), as measured by Coulter Counter.

[0161] Preparation of Microcapsules

[0162] A suspension of core particles in water is prepared, bydispersing 50 grams of core particles in 500 ml demineralized water.

[0163] In a separate vessel a solution of 8.5 grams of polyvinylpyrrolidone (Kollidon K15) in 100 ml of water is prepared.

[0164] The solution of polyvinyl pyrrolidone is added to the suspensionof core particles and immediately spray dried at 65° C. to formmicrocapsules consisting of core particles encapsulated by a thin filmof polyvinyl pyrrolidone (˜0.35 micron).

[0165] Surface Treatment

[0166] The microcapsule particles, having the core-shell structure, arepremixed with the surface additives using the Ordered Mixing stage of aNara Hybridizer (Nara Machinery Company). The ordered mixture issubjected to two consecutive high shear mixing cycles in the NaraHybridizer (Hybridizer Stage) to effectively embed the additiveparticles onto the surface of the microcapsules.

[0167] Application to Substrate

[0168] The powder from the above Examples is coated on to pharmaceuticaltablets by the method described in WO 96/35516, WO 96/35413 orPCT/US00/33962.

1. A method of electrostatically applying powder material to asubstrate, wherein at least some of the particles of the materialcomprise a core and a shell surrounding the core, the material of thecore and the shell having different physical and/or chemical properties.2. A method according to claim 1, wherein the core comprises acharge-control agent.
 3. A method according to claim 1 or claim 2,wherein the shell comprises a charge-control agent.
 4. A methodaccording to claim 2 or claim 3, wherein the powder material containsfrom 1 to 2% by weight of charge-control agent.
 5. A method according toany one of claims 1 to 4, wherein the shell comprises a component thatis fusible.
 6. A method according to any one of claims 1 to 5, whereinthe core comprises a component that is fusible.
 7. A method according toclaim 5 or claim 6, wherein the fusible component(s) are treatable toform a continuous film coating at a temperature of no more than 150° C.at a pressure of no more than 100 lb/sq inch.
 8. A method according toany one of claims 5 to 7, wherein the powder material contains at least35% by weight of fusible component.
 9. A method according to claim 8,wherein the powder material contains at least 80% by weight of fusiblecomponent.
 10. A method according to any one of claims 5 to 9, whereinthe powder material contains a binder polymer.
 11. A method according toclaim 10, wherein the powder material contains a methacrylate orpolyvinylpyrrolidone.
 12. A method according to claim 10, wherein thepowder material contains a binder polymer having charge-controlfunctionality.
 13. A method according to any one of claims 5 to 12,wherein the powder material contains wax.
 14. A method according toclaim 13, wherein the powder material contains no more than 6% by weightof wax.
 15. A method according to claim 14, wherein the powder materialcontains from 1 to 6% by weight of wax.
 16. A method according to claim15, wherein the powder material contains from 1 to 3% by weight of wax.17. A method according to any one of claims 1 to 16, wherein the corecomprises a colorant and/or an opacifier.
 18. A method according to anyone of claims 1 to 17, wherein the shell comprises a colorant and/or anopacifier.
 19. A method according to claim 17 or claim 18, wherein thepowder material contains no more than 30% by weight of colorant andopacifier.
 20. A method according to claim 19, wherein the powdermaterial contains no more than 25% by weight of colorant and opacifier.21. A method according to any one of claims 17 to 20, wherein the powdermaterial contains titanium dioxide.
 22. A method according to any one ofclaims 17 to 21, wherein the powder material contains from 1 to 15% byweight of colorant.
 23. A method according to claim 22, wherein thepowder material contains from 2 to 5% by weight of colorant.
 24. Amethod according to any one of claims 1 to 23, wherein the core containsa dispersing agent.
 25. A method according to any one of claims 1 to 24,wherein the powder material contains from 1 to 5% by weight ofdispersing agent.
 26. A method according to any one of claims 1 to 25,wherein the core contains a disintegrant.
 27. A method according to anyone of claims 1 to 26, wherein the powder material contains from 0.5 to1% by weight of disintegrant.
 28. A method according to any one ofclaims 1 to 27, wherein the powder material contains a taste modifier.29. A method according to any one of claims 1 to 28, wherein the corecontains a placticiser.
 30. A method according to any one of claims 1 to29, wherein the powder material contains at least 2% by weight ofplasticiser, plasticiser being used with a binder polymer in an amountof up to 50% by weight of the total weight of that plasticiser and thatbinder polymer.
 31. A method according to any one of claims 1 to 30,wherein the powder material contains filler.
 32. A method according toany one of claims 1 to 31, wherein at least one component is present onthe outer surface of the shell.
 33. A method according to claim 32,wherein a flow aid is present on the surface of the shell.
 34. A methodaccording to claim 33, wherein the powder material contains from 0.2 to2.5% by weight of flow aid.
 35. A method according to claim 33 or claim34, wherein silica and titanium dioxide are present as flow aid.
 36. Amethod according to any one of claims 1 to 35, wherein at least 50% byvolume of the particles of the material have a particle size in therange of from 5 μm to 40 μm.
 37. A method according to claim 36, whereinat least 50% by volume of the particles of the material have a particlesize in the range of from 10 to 25 μm.
 38. A method according to any oneof claims 1 to 37, wherein the d₉₀/d₅₀ ratio for the powder material isin the range of from 1.2 to 1.5.
 39. A method according to claim 38,wherein d₉₀/d₅₀ is in the range of from 1.25 to 1.35.
 40. A methodaccording to claim 39, wherein d₉₀/d₅₀ is in the range of from 1.27 to1.32.
 41. A method according to any one of claims 1 to 40, wherein theshell has a thickness in the range of from 0.1 μm to 5 μm.
 42. A methodaccording to claim 41, wherein the shell has a thickness in the range of0.1 μm to 1.5 μm.
 43. A method according to claim 42, wherein the shellhas a thickness in the range of 0.2 μm to lam.
 44. A method according toany one of claims 1 to 43, wherein the powder material is fusible at atemperature of no more than 150° C. at atmospheric pressure to form acontinuous film coating.
 45. A method according to claim 44, wherein thepowder material is fusible at atmospheric pressure at a temperature inthe range of from 120 to 140° C.
 46. A method according to claim 44 orclaim 45, wherein the fused powder material is soluble in aqueous media.47. A method according to any one of claims 1 to 45, wherein the powdermaterial contains polymer binder that is insoluble in aqueous media. 48.A method according to any of claims 1 to 47, wherein the powder materialhas a Tg in the range of from 40° C. to 120° C.
 49. A method accordingto claim 48, wherein the powder material has a Tg in the range of from50° C. to 100° C.
 50. A method according to claim 49, wherein the powdermaterial has a Tg in the range of from 55° C. to 70° C.
 51. A methodaccording to any one of claims 1 to 50, wherein at least one componentpresent in the core is not present in the shell.
 52. A method accordingto any one of claims 1 to 51, wherein at least one component present inthe shell is not present in the core.
 53. A method according to any oneof claims 1 to 52, wherein the core comprises a binder polymer and oneor more additives selected from a colorant, an opacifier, a biologicallyactive material and a filler and optionally one or more other additives,and the shell comprises a binder polymer and optionally one or moreother additives.
 54. A method according to any one of claims 1 to 53,wherein the shell comprises a binder polymer and optionally othernon-binder fusible material, colorant, dispersing agent orcharge-control agent or two or more such components, and wherein thecore comprises a binder polymer and colorant, opacifier, dispersingagent, charge-control agent, disintegrant, wax, other non-binder fusiblematerial, plasticiser or taste-modifier or two or more such components.55. A method according to claim 53 or claim 54, wherein the powdermaterial includes a polymer material having a charge-controlfunctionality and/or a separate charge-control additive.
 56. A methodaccording to claim 55, wherein material having charge-control functionalis present in the core.
 57. A method according to claim 56, wherein acharge-control agent is present in the core and not in the shell.
 58. Amethod according to any one of claims 53 to 57, wherein a flow aid ispresent on the outer surface of the shell.
 59. A method according to anyone of claims 1 to 58, wherein the powder material includes activematerial for release in the environment in which the substrate isapplied.
 60. A method according to claim 59, wherein the powder materialcontains biologically active material.
 61. A method according to claim59 or claim 60, wherein active material is present in the core.
 62. Amethod according to any one of claims 59 to 61, wherein the powdermaterial also includes filler.
 63. A method according to claim 61,wherein active material and filler are present in the core.
 64. A methodaccording to any one of claims 59 to 63, wherein the powder materialcontains up to 50% by weight of active material.
 65. A method accordingto any one of claims 59 to 64, wherein the substrate contains adifferent active material from the powder material.
 66. A methodaccording to any one of claims 59 to 65, wherein the substrate containsthe same active material as the powder material.
 67. A method accordingto any one of claims 59 to 64, wherein the substrate contains no activematerial.
 68. A method according to any one of claims 1 to 67, whereinthe substrate is a pharmaceutical substrate and the powder material ispharmaceutically acceptable.
 69. A method according to any one of claims1 to 68, wherein the substrate is a solid dosage form.
 70. A methodaccording to claim 69, wherein the substrate is a pharmaceutical soliddosage form and the powder material is pharmaceutically acceptable. 71.A method according to claim 70, wherein the pharmaceutical solid dosageform is for human use.
 72. A method according to claim 71, wherein thepharmaceutical solid dosage form is a tablet core.
 73. A powder materialsuitable for electrostatic application to a substrate, wherein at leastsome of the particles of the material comprise a core and a shellsurrounding the core, the material of the core and the shell havingdifferent physical and/or chemical properties.
 74. A pharmaceuticallyacceptable powder material suitable for electrostatic application to apharmaceutical substrate, wherein at least some of the particles of thematerial comprise a core and a shell surrounding the core, the materialof the core and the shell having different physical and/or chemicalproperties.
 75. A powder material suitable for electrostatic applicationto a substrate, wherein at least some of the particles of the materialcomprise a core and a shell surrounding the core, the material of thecore and the shell having different physical and/or chemical properties,and which includes biologically active material.
 76. A powder materialaccording to claim 74 or 75, which includes physiologically activematerial.
 77. A powder material according to claim 75 or claim 76, whichhas one or more of the features specified in claims 61 to
 64. 78. Apowder material according to any one of claims 73 to 77, which is asspecified in any one of claims 2 to
 58. 79. A powder material suitablefor electrostatic application to a substrate, wherein at least some ofthe particles of the material comprise a core and a shell surroundingthe core, the material of the core and the shell having differentphysical and/or chemical properties, wherein at least one componentpresent in the core is not present in the shell and at least onecomponent present in the shell is not present in the core and whereinthe powder material is fusible at a temperature of no more than 150° C.at atmospheric pressure to form a continuous film coating, is soluble inaqueous media and includes a charge-control agent or a polymer havingcharge-control functionality
 80. A method of applying powder materialaccording to any one of claims 73 to 79 to a substrate, which comprisesan electrostatic application step.
 81. A substrate to which powdermaterial has been electrostatically applied by a method according to anyone of claims 1 to 72 and
 80. 82. A substrate according to claim 81,wherein the powder material has been fused to form a continuous filmcoating.
 83. A method of preparing a range of powder materials forelectrostatic application to pharmaceutical substrates, the particles ofeach of the powder materials comprising a core and a shell surroundingthe core, which method comprises, for each powder material,encapsulating the desired core material, the core material comprising abinder polymer and one or more additives selected from a colorant, anopacifier, a biologically active material and a filler and optionallyone or more other additives, with a shell material having differentphysical and/or chemical properties from the core material andcomprising a binder polymer and optionally one or more other additives,and wherein the same shell material is used for the range of powdermaterials produced.